A recent study in Nature Communications introduces a hydrogel (OSPPB) designed to mitigate osteoarthritis (OA) by scavenging extracellular RNA and releasing bevacizumab to inhibit neurovascularization at the osteochondral interface. This approach aims to reduce pain and slow disease progression.
The hydrogel is formed by cross-linking aldehyde-phenylboronic acid-modified sodium alginate (OSAP) with polyethyleneimine-grafted protocatechuic acid (PPCA) and incorporating bioactive glass nanoparticles (BGNs) loaded with bevacizumab.
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Background
OA is a widespread musculoskeletal condition with high morbidity. Research has identified neurovascularization at the osteochondral interface as a key factor in OA-related pain and disease progression. Despite this, treatments targeting neurovascularization remain underexplored.
Responsive hydrogels, which release drugs in response to environmental changes, offer a promising approach for OA treatment. These hydrogels allow controlled release of polycationic agents, reducing toxicity and improving therapeutic outcomes. Given the significant changes in the osteochondral microenvironment during OA, a hydrogel responsive to pH and reactive oxygen species (ROS) could provide targeted drug delivery while supporting tissue restoration.
This study introduces a dual-responsive hydrogel that releases active ingredients as needed, inhibits neurovascularization, and promotes structural restoration.
Methods
To create the OSPPB hydrogel, OSAP was cross-linked with PPCA through dynamic boronic ester and Schiff base bonds. When the polymer solutions were mixed, the hydrogel formed within three seconds. Bevacizumab-loaded BGNs (BGN@Be) were incorporated through coordination interactions.
The synthesis of the polymers and hydrogels was confirmed using attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR). The hydrogel’s structure was analyzed with field-emission scanning electron microscopy (FESEM), and its elemental composition and BGN@Be distribution were characterized using energy-dispersive X-ray spectroscopy (EDS).
Rheological properties were measured at 25 °C using a rheometer, while in vitro degradation was tested in phosphate-buffered saline (PBS) at 37 °C. Anti-inflammatory properties were assessed using a 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity assay.
Additional experiments included binding tests with Cy3-RNA and vascular endothelial growth factor (VEGF), hemolysis evaluation using heparinized mouse blood, and in vivo studies on 48 female C57BL/6J mice and 30 Sprague-Dawley rats.
Results and Discussion
The OSPPB hydrogel, comprising OSAP, PPCA, and BGN@Be, was formed through reversible Schiff base and boronic ester bonds, with additional Ca2+ coordination between BGN and OSAP. These bonds allowed the hydrogel to be self-healing, injectable, and dual-responsive, enabling controlled drug release.
The hydrogel effectively scavenged extracellular RNA through polycationic PPCA and neutralized VEGF activity via BGN@Be. This combination not only suppressed neurovascular factors but also disrupted their recruitment process, significantly inhibiting neurovascularization at the osteochondral interface. In vitro analysis showed a notable reduction in the activity of trigeminal ganglion and endothelial progenitor cells.
Histological and microstructural analyses confirmed that OSPPB treatment improved temporomandibular joint (TMJ) OA. Additionally, OSPPB hydrogel demonstrated pain relief comparable to celecoxib, a commonly used nonsteroidal anti-inflammatory drug.
Pain behavior tests in rodents showed that mice treated with either celecoxib or OSPPB experienced significant relief from maxillofacial pain. Furthermore, key pain mediators such as cyclooxygenase 2, DCC netrin 1 receptor, and substance P were notably reduced following OSPPB treatment.
While celecoxib primarily alleviated pain, its effect on the regenerative microenvironment was limited. In contrast, the OSPPB hydrogel not only reduced pain but also suppressed neurovascularization and prevented joint destruction, demonstrating its potential for long-term OA management.
Conclusion
This study successfully developed a pH- and ROS-responsive, injectable, self-healing hydrogel to treat OA by inhibiting neurovascularization at the osteochondral interface. The positively charged OSPPB hydrogel could penetrate the cartilage matrix and function effectively in the joint environment.
Upon exposure to high ROS and low pH, the hydrogel’s dynamic Schiff base and boronic ester bonds rapidly cleaved, releasing active components. This process facilitated extracellular RNA scavenging, controlled bevacizumab release, and direct inhibition of neurovascularization, ultimately reducing pain and reversing OA-related anatomical changes.
Although these findings are preliminary, the OSPPB hydrogel demonstrates significant potential for treating TMJ-OA and could be adapted for use in other joints affected by OA.
Journal Reference
Qin, W., et al. (2025). Neurovascularization inhibiting dual responsive hydrogel for alleviating the progression of osteoarthritis. Nature Communications, 16(1). DOI: 10.1038/s41467-025-56727-8, https://www.nature.com/articles/s41467-025-56727-8
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